This program project has two objectives: to use molecular biology and genetics to elucidate the life cycles of and transformation by human tumor viruses and to translate this understanding into the identification of targets for specific anti-viral, anti-tumor therapies. This program includes six investigators who share these research goals in studying four human tumor viruses that together account for the majority of human cancers caused by viruses. Our program has evolved to foster two or more investigators working together on individual projects and to cross-fertilize these projects by multiple investigators working on pairs of projects. This evolution has been made possible by collaborations that have developed among current investigators and with new investigators. Dr. Kenney has moved from the Lineberger Cancer Center and joined our team to understand Epstein-Barr Virus's (EBV) pathogenicity through her fundamental research and her clinical expertise. Dr. Janet Mertz has identified and characterized cellular factors that regulate expression of viral genes and is collaborating with Dr. Kenney to define the mechanisms that control the switch from EBV's latent to lytic cycle. A tenet of their work is that inducing EBV's lytic cycle efficiently in tumors would be therapeutically beneficial. Drs. Kenney and Mertz are collaborating with Dr. Sugden to uncover EBV's functions necessary to sustain its lymphomas. They are also examining virally associated pathways and their inhibitors, some now used in clinical trials, as targets for developing therapies and as possible therapies now. Dr. Sugden is collaborating with Dr. Lambert to study the plasmid replication of EBV, Kaposi's Sarcoma Herpes Virus (KSHV), and human papillomavirus (HPV) type 16 both to understand them and ultimately to identify features that render them vulnerable to inhibition. Dr. Lambert is collaborating with Dr. Ahlquist to study HPV16 in transgenic mouse models and human cancer patients to identify the mechanisms of HPV infection, oncogene action, and tumor progression. Dr. Ahlquist is collaborating with Dr. Loeb to combine findings of their large-scale cell screens and robust cellular models to dissect the viral and cellular contributions to the replication of human hepatitis B virus (HBV). All of these collaborations will illuminate how these human tumor viruses replicate. All will identify and characterize steps in viral life cycles, viral oncogenic functions, and cellular cofactors that are targets for therapeutic intervention.